Functional Heterodimerization of Prolactin and Growth Hormone Receptors by Ovine Placental Lactogen

Abstract

Although homo-or heterodimerization are common mechanisms for activation of cytokine receptors, crosstalk between two distinct receptors in this superfamily has been never shown. Here we show a physiologically relevant example indicating that such an interaction does occurs, thus raising the hypothesis that heterodimerization between distinct cytokine receptors may be a novel mechanism contributing to the diversity of cytokine signaling. These findings were documented using both surface plasmon resonance and gel filtration experiments and show that ovine placental lactogen (PL) heterodimerizes the extracellular domains (ECDs) of ruminant growth hormone receptor (GHR) and prolactin receptor (PRLR). We also show that PL or PL analogues that exhibit little or no activity in cells transfected with PRLRs and no activity in cells transfected with ovine GHRs exhibit largely enhanced activity in cells cotransfected with both PRLRs and GHRs. Furthermore, chimeric receptors consisting of cytosolic and transmembrane part of ovine GHR or ovine PRLR and ECDs of human granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) ␣ or ␤ were constructed. Upon transfection into Chinese hamster ovary cells along with reporter luciferase gene and stimulation by GM-CSF, a significant increase in luciferase activity occurred when GM-CSFR-␣-PRLR and GM-CSFR-␤-GHR or GM-CSFR-␣-GHR and GM-CSRR-␤-PRLR were cotransfected. In conclusion, we show that ovine PL is capable of functional heterodimerization of GHR and PRLR and that when their cytosolic parts, coupled to the ECD of GM-CSF receptors, are heterodimerized by GM-CSF, they are capable of transducing biological signal.

Episodic evolution of prolactin receptor gene in mammals: coevolution with its ligand

“…Most other mammalian groups, including pig, rabbit and dog, do not appear to have such a cluster (Talamantes et al 1980, Forsyth & Wallis 2002, and in the case of dog this was confirmed by a BLAST search of the genome sequence. Placental lactogens appear to use the PRLR signaling pathway (Golos et al 1993, Soares et al 1998, Herman et al 2000, Biener et al 2003 like pituitary PRL. This might suggest that the episodic evolution observed for the PRLR reflects adaptation to the presence of multiple ligands.…”

Interferon-τ upregulates prolactin receptor mRNA in the ovine endometrium during the peri-implantation period

“…Furthermore, enhancing the bioactivity of ovine PL results in increased birth weight of lambs and milk production by the ewes (Leibovitch et al 2000). It is now established that ruminant PLs have the ability to bind both PRL-R and GH receptor (GH-R) (Herman et al 2000). Several studies provide evidence that a transient homodimerization of PRL-R occurs in response to ruminant PL (Gertler et al 1996, Sakal et al 1997 and, more recently, the functional heterodimerization of PRL-R and GH-R by PL has been demonstrated in vitro (Herman et al 2000, Biener et al 2003 and in the ovine endometrium (Noel et al 2003).…”

“…It is now established that ruminant PLs have the ability to bind both PRL-R and GH receptor (GH-R) (Herman et al 2000). Several studies provide evidence that a transient homodimerization of PRL-R occurs in response to ruminant PL (Gertler et al 1996, Sakal et al 1997 and, more recently, the functional heterodimerization of PRL-R and GH-R by PL has been demonstrated in vitro (Herman et al 2000, Biener et al 2003 and in the ovine endometrium (Noel et al 2003). Although it has been established that GH-R was expressed throughout pregnancy in the endometrium (Lacroix et al 1999), no precise quantitative study has been reported for GH-R mRNA expression during the peri-implantation period.…”

Reconsideration of the proposed luteotropic and luteoprotective actions of ovine placental lactogen in sheep: in vivo and in vitro studies

“…Specific binding sites for oPL have been detected in various tissues, including the CL, obtained from nonpregnant and pregnant ewes (Chan et al 1978b). Evidence indicates that the ovine prolactin (oPRL) receptor transduces signals by oPL, because this hormone homodimerizes the oPRL receptor and activates signaling pathways (Herman et al 2000). In addition, one property of ruminant PLs is their ability to bind both PRL and growth hormone (GH) receptors (for review, see Gertler & Djiane 2002).…”